In response to cAMP stimulation, CREB is phosphorylated at Ser 133 via the cAMP dependent protein kinase (PKA). Phosphorylated CREB stimulates target gene expression, in part, via the recruitment of the signal dependent co-activators C P300. In addition to cAMP, a number of second messenger pathways including the phospho-inositol pathway have been sh induce Ser 133 phosphorylation. But, these pathways do not appear to stimulate target gene expression via CREB, suggesti PKA provides an additional signal (referred as the second event) that stimulates CREB activation. Thus, the experiments proposal are designed to identify the mechanism underlying the second event. Specifically, I will test two alternative models: the negative signal corresponds to a phosphorylation or dephosphorylation event in KID or KIX; 2) that the negative corresponds to an inhibiting protein which blocks complex between these two domains. CREB has been shown to involve different biological processes including cell growth, differentiation, the formation of long-term memory and meta Understand the signal transduction pathways that regulate CREB activities will have important implication for these bi processes.